title: Activation of AMPK enhances neutrophil chemotaxis and bacterial killing.
abstract: An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5' adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Division of Infectious Diseases, Korea University Ansan Hospital, Ansan, Republic of Korea.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Park
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Shaoning
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Service des Maladies Infectieuses et Réanimation Médicale, Centre Hospitalier Universitaire, Rennes, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Tadie
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Stigler
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jessy
authors.initials: J
authors.lastname: Deshane
authors.affiliation: Office of the Dean, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016470:Bacteremia / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004789:Enzyme Activation; D018922:HL-60 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D010538:Peritonitis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000199:Actins; D006575:Heterocyclic Compounds, 3-Ring; C456319:PS1145; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus